Restoring CD4 counts to ‘normal’ levels is possible within seven years if individuals begin antiretroviral therapy at CD4 counts above 350 cells/mm3, according to a Dutch study published in the June 1st issue of the Journal of Acquired Immune Deficiency Syndromes (JAIDS). An accompanying editorial calls for a “broader re-evaluation of the ideal time to start therapy, incorporating outcomes other than survival, such as the level of immune reconstitution” and the effect on HIV transmission.
The call to initiate Highly Active Antiretroviral Therapy (HAART) earlier – the so-called pendulum swing back towards the late 90s ‘hit hard, hit early’ approach – began late in 2004, following the publication of an an editorial by four US HIV clinicians in the journal, Clinical Infectious Diseases. The concept has taken some time to gain momentum, but several studies have since shown a survival benefit to earlier treatment, as highlighted in a BMJ editorial earlier this year.
With this month’s publication of a study from the AIDS Therapy Evaluation Project, Netherlands (ATHENA), first presented at the 2006 Conference on Opportunistic Infections and Retroviruses (CROI) in Denver, Dr Julio Montaner of the British Columbia Centre for Excellence in HIV/AIDS, adds his voice to the call for the earlier initiation of HAART.
Dr Montaner and his Vancouver colleague, Dr Evan Wood, point out that most previous studies “have focused on the impact of HAART...on survival, whereas issues other than survival have received little attention.” They note that the ATHENA study “demonstrate[s] elegantly that many patients on long-term HAART regain CD4 counts greater than 800 cells/mm3.”
The ATHENA study chose the endpoint of 800 cells/mm3 because it is the average (mean) CD4 count in gay men, who made up a large proportion of the ATHENA cohort, rather than 500 cells/mm3, which is the lower limit of the normal range in HIV-negative individuals.
“More importantly,” they write, “they demonstrate a strong association between pretreatment CD4 cell count and enhanced CD4 cell count recovery among patients initiating HAART with higher CD4 cell counts.”
The study found that among participants with a baseline CD4 count in the 200-350 cells/mm3 range, 46% achieved 800 cells/mm3 within seven years, “whereas,” they note, “this jumped to 73% among those with baseline CD4 cell counts of 350 to 500 cells/mm3.”
Individuals who began HAART with a CD4 count between 350-500 cells/mm3 were 2.84 more likely to achieve a ‘normal’ CD4 cell count within seven years. Female gender and higher pre-HAART viral loads were associated with a shorter time to CD4 cell counts above 800 cells/mm3, whereas older age, Southeast Asian or sub-Saharan African origin, and HIV infection through intravenous drug use were associated with a longer time to a ‘normal’ CD4 cell count.
The authors of the ATHENA study conclude that “HAART restoration of CD4 cell counts in HIV-infected individuals to levels normally seen in uninfected individuals takes a long time and is not feasible within seven years in most patients who initiate HAART with CD4 cell counts 3...Given the better toxicity profiles of the currently used antiretroviral combinations, particularly in patients older than 50 years of age, it may be beneficial to start HAART earlier than current guidelines recommend.”
Although Montaner and Woods admit that “the clinical implications of these findings have yet to be determined, because most HIV-related complications are not observed until the CD4 cell count declines to less than 200 cells/mm3, they point out that the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study had found that liver-related death as well as cancer-associated mortality in HIV-positive individuals is associated with lower CD4 counts. “Of interest,” they write, “this study noted differences in these specific endpoints even between those in the 200 to 350 cells/mm3 and >350 cells/mm3 categories.”
They also point out that the SMART study found an increased risk of disease progression in the treatment interruption arm compared with participants who remained on HAART “despite the fact that almost all participants in the trial had CD4 counts greater than 200 cells/mm3 during follow-up. Interestingly, although HAART is associated with the range of side effects described previously, the SMART trial indicated that patients in the CD4 cell count-guided interrupted antiretroviral therapy arm had increased risk of certain health outcomes (combined endpoint: myocardial infarction, stroke, liver cirrhosis, and renal failure) compared with those on continuous HAART treatment.”
They argue that “newer regimens tend to be simpler and safer. This progressively opens the door for a broader re-evaluation of the ideal time to start therapy, incorporating outcomes other than survival, such as the level of immune reconstitution demonstrated [in the ATHENA study].”
They also suggest that “there is growing evidence that HAART-treated patients are less likely to transmit HIV infection to others. Recently, mathematic modeling has suggested that expansion of HAART programs could play a substantial role in decreasing HIV incidence. So far, the added preventive value of HAART has not been incorporated into the equation when evaluating the ideal time to start therapy.”
“Given the potential effect that HAART can have in various domains other than survival,” they conclude, “we must broaden our focus to incorporate a variety of appropriately weighted patient outcomes, and their public health consequences.”
Gras L et al. CD4 cell counts of 800 cells/mm3 or greater after 7 years of Highly Active Antiretroviral Therapy are feasible in most patients starting with 350 cells/mm3 or greater. Journal of Acquired Immune Deficiency Syndromes 45(2); 183-192, 2007.
Wood E and Montaner JSG. When to initiate HIV antiretroviral therapy: do benefits other than survival deserve greater attention? Journal of Acquired Immune Deficiency Syndromes 45(2); 131-132, 2007.